Selective induction of mitochondrial cell death pathway by LAQ 824, a histone deacetylase inhibitor

1369 Histone deacetylase inhibitors have shown considerable potential as new anti-tumor agents due to their ability to induce cell cycle arrest and cell death. To elucidate the molecular mechanism of the selective induction of apoptosis by HDAC inhibition in cancer cells, we have investigated the different sensitivity of cancer and normal cells to LAQ824, a pan-HDAC inhibitor. We found that LAQ824 selectively induced cell death in cancer cells but not in normal cells. Furthermore, we have demonstrated the underlying mechanism for this selectivity and provide a model for LAQ824 induced apoptosis in cancer cells. We reveal that LAQ824 increases the levels of expression and activity of two key proapoptotic proteins, caspase 9 and Apaf1, and promotes the release of mitochondrial proapoptotic factors such as cytochrome c and AIF in cancer cells but not in normal cells. As an important step toward understanding the role of HDAC in apoptosis, we performed lenti-virus mediated knockdown of HDAC1 and HDAC2. We found that the inhibition of HDAC2 in human lung cancer cells sensitized them to LAQ824 induced apoptosis, indicating that HDAC2 plays an important role in HDAC inhibitor induced cell death. Our results suggest that HDAC2 is a potential candidate both as a marker for tumor progression and a target for cancer therapy. Our data also provide a mechanistic rationale for the development of HDAC2-specific inhibitors to improve efficacy and reduce side effects of current pan-HDAC inhibitors.